Schizophrenia Research 40 (1999) 11–21 www.elsevier.com/locate/schres Ventriculomegaly and reduced hippocampal volume following intrauterine growth-restriction: implications for the aetiology of schizophrenia E. Carina Mallard, PhD a, Alexandra Rehn, BSc ( Hons) a, Sandra Rees, MPhil, PhD a, *, Mary Tolcos, BSc (Hons) a, David Copolov, MBBS, PhD, FRACP, FRANZCP b a Department of Anatomy and Cell Biology, The University of Melbourne, Parkville, Vic. 3052, Australia b Mental Health Research Institute of Victoria, Locked bag 11 Parkville, Vic. 3052, Australia Received 30 October 1998; accepted for publication 10 March 1999 Abstract Structural alterations in the brains of some schizophrenic patients suggest an impairment of brain development, possibly as a result of intrauterine compromise. In this study we have tested the hypothesis that placental insufficiency during the second half of pregnancy in the guinea pig results in structural alterations similar to those seen in some schizophrenic patients. Placental insufficiency was induced in pregnant guinea pigs via uterine artery ligation at midgestation. At 60 days gestation (term: 68 days gestation) the fetal brains were prepared for quantitative histological and immunohistochemical analysis and compared with controls. Placental insufficiency resulted in growth-restricted animals with significantly larger cerebral ventricles, reduced cross-sectional area of the cerebral cortex and the striatum and reduced hippocampal volume compared with controls. There were fewer neuronal nitric oxide synthase (nNOS )- positive cells in layers 5–6 of the cingulate cortex, and in layer 1 of the frontal and temporal cortices. In contrast, there were no significant alterations in the optical density of tyrosine hydroxylase (TH ), a rate-limiting enzyme in the biosynthesis of catecholamines and the dopamine transporter (DAT ) in the striatum in growth-restricted animals compared with controls. These findings indicate that developmental disturbances can produce anatomical changes that resemble those found in some individuals with schizophrenia. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Brain development; Dopamine transporter (DAT ); Immunohistochemistry; Neuronal nitric oxide synthase (nNOS); Placental insufficiency; Tyrosine hydroxylase (TH ) 1. Introduction as a result of adverse events occurring during fetal or early postnatal life (for example, Waddington, 1993; Readler et al., 1998). Although the role of It has been suggested that brain development is such early events has been challenged by a number impaired in some schizophrenic patients, possibly of studies (for example, Done et al., 1991; Crow and Done, 1992; McReadie et al., 1992; Buka et al., 1993; Cannon et al., 1996), a recent meta- * Corresponding author. Tel.: +61-3-9344-5797; analysis suggests that the balance of studies do fax: +61-3-9347-5219. E-mail address: s.rees@anatomy.unimelb.edu.au (S. Rees) show, for example, an increased incidence of 0920-9964/99/$ – see front matter © 1999 Elsevier Science B.V. All rights reserved. PII: S0920-9964(99)00041-9